Imperial College London
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ProfessorJulianGriffin

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 3220julian.griffin

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Azzu:2021:10.1016/j.molmet.2021.101210,
author = {Azzu, V and Vacca, M and Kamzolas, I and Hall, Z and Leslie, J and Carobbio, S and Virtue, S and Davies, SE and Lukasik, A and Dale, M and Bohlooly-Y, M and Acharjee, A and Lindén, D and Bidault, G and Petsalaki, E and Griffin, JL and Oakley, F and Allison, MED and Vidal-Puig, A},
doi = {10.1016/j.molmet.2021.101210},
journal = {Molecular Metabolism},
pages = {1--10},
title = {Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression},
url = {http://dx.doi.org/10.1016/j.molmet.2021.101210},
volume = {48},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. METHODS AND RESULTS: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. CONCLUSIONS: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.
AU  - Azzu,V
AU  - Vacca,M
AU  - Kamzolas,I
AU  - Hall,Z
AU  - Leslie,J
AU  - Carobbio,S
AU  - Virtue,S
AU  - Davies,SE
AU  - Lukasik,A
AU  - Dale,M
AU  - Bohlooly-Y,M
AU  - Acharjee,A
AU  - Lindén,D
AU  - Bidault,G
AU  - Petsalaki,E
AU  - Griffin,JL
AU  - Oakley,F
AU  - Allison,MED
AU  - Vidal-Puig,A
DO  - 10.1016/j.molmet.2021.101210
EP  - 10
PY  - 2021///
SN  - 2212-8778
SP  - 1
TI  - Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression
T2  - Molecular Metabolism
UR  - http://dx.doi.org/10.1016/j.molmet.2021.101210
UR  - https://www.ncbi.nlm.nih.gov/pubmed/33722690
UR  - https://www.sciencedirect.com/science/article/pii/S2212877821000508
UR  - http://hdl.handle.net/10044/1/88498
VL  - 48
ER  -
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